Nonsyndromic cleft lip and palate (NSCLP) is a common birth defect affecting approximately 4,000 newborns each year in the US and a million worldwide. Multidisciplinary approaches have improved the care of these children but long-term problems persist and are related to facial dysmorphism and speech impediments. The health care costs are significant. Numerous studies support the idea that NSCLP is a complex disorder and that genetic factors play an important etiologic role in its development. The challenge now is to identify the NSCLP loci. Towards this goal, we have amassed a collection of multiplex families and simplex trios and we have employed a combination of candidate gene and genome scan approaches to successfully identify 12 chromosomal regions and several candidate genes to interrogate. Most exciting is the identification of a 20cM region on chromosome 8 with a maximum LOD score of 2.84 in a single large African-American family. In these continuing studies, we will further refine the identified chromosomal regions and fully characterize our candidate genes. We will continue to collect NSCLP families and simplex NSCLP trios to further expand our data set and will assemble a population based case-control data set for use in confirmatory studies. Finally we will submit our expanded sample set to a high-density genome scan during the third year of the funding cycle. The results of this study will provide data essential to the identification of the gene(s) contributing to the NSCLP phenotype. Identification of high-risk genotypes can lead to the development of prevention programs in selected populations and may suggest gene-based prevention strategies.